The present invention relates to a series of new cephalosporin derivatives having an aryloxymethyl, more specifically an optionally substituted phenoxymethyl, group at the 3-position and having an amino or optionally substituted acylamino group at the 7-position. These compounds are cephalosporin antibiotics or are precursors in the preparation of cephalosporin antibiotics having a wide spectrum of antibacterial activity. The invention also provides a method for preparing these new compounds and processes and compositions using them.
Since the first discovery of the cephalosporin family of antibiotics, which really began in the 1950's, considerable interest has been shown in this range of antibiotics and many of them have been found to be of considerable practical use in the treatment of microbial infections. The earliest members of the cephalosporin family to find practical use, which might be termed "the first generation", started to become generally available in the 1970's and are typified by Cefazolin. These antibiotics were extremely good for their time but were and are susceptible to microorganisms capable of producing .beta.-lactamase, and these microorganisms were thus resistant to them, with the result that the value of the first generation cephalosporin antibiotics decreased with time. The next group of cephalosporin antibiotics, which may be termed "the second generation", overcame this problem of resistance by microorganisms which produce .beta.-lactamase and are typified by Cefmetazole and Cefothiam. In recent years, we have seen the emergence of a third generation of cephalosporin antibiotics, which are distinguished from the second generation by their broader antibacterial spectrum of activity, especially against Gram-negative bacteria. Many hopes are pinned on this third generation, most particularly to find an antibiotic which is active against Methicillin-resistant strains of Staphylococcus, which have been the cause of many deaths, especially in hospitals, and much difficulty and distress for patients and medical practitioners. Hitherto, so far as we are, at the time of writing, aware, this search has proved fruitless.
We have now surprisingly found a series of cephalosporin derivatives which have a wide spectrum of antibacterial activity and to which, quite unexpectedly, Methicillin-resistant strains of Staphylococcus appear to be susceptible. The compounds are also believed to have a sufficiently low toxicity to humans and other animals that it is expected that they will find practical therapeutic use. The compounds of the present invention are characterised by the presence of an optionally substituted phenoxymethyl group at the 3-position.
Surprisingly, compounds having such an optionally substituted phenoxymethyl group at the 3-position do not appear to have been disclosed in the past, although such compounds are covered by general references to a wide range of groups at the 3-position in a number of prior patents, for example Japanese Patent Application No. Kokai (i.e. as laid open to public inspection prior to examination) No. Sho. 60-41681. However, it appears to be the presence of this group that leads to the unexpected activity of the compounds of the present invention.